Increasing numbers of newly discovered drugs are insoluble (e.g., have a solubility of less than 100 μg per mL as per the definition of United States Pharmacopeia). For example, pharmaceutical compounds such as itraconazole, saquinavir, cyclosporine, paclitaxel, etoposide, etc. have an extremely low solubility in water. Indeed, the solubility of itraconazole in water and 0.1 N hydrochloric acid is less than 1 microgram and 6 micrograms per milliliter, respectively. Saquinavir, an antiviral compound, has approximately 10 microgram per mL solubility in water.
PCT Application WO 94/05263 to Gillis et al. (assigned to Janssen Pharmaceutica) describes 25-30 mesh beads having a core coated with itraconazole or saperconazole, which beads may be used to produce dosage forms of these drugs. To prepare the beads, the drug coating solution is dissolved into a suitable solvent system which is then combined with the beads. However, the only solvent system described is one comprising methylene chloride (dichloromethane) and an alcohol (see page 4, line 4 therein). Methylene chloride is undesirable as a solvent in pharmaceutical systems due to potential toxicological concerns.
PCT Application WO 00/03697 to Gillis et al. (assigned to Janssen Pharmaceutica) describes usage of sugar pellets of 710-1180 μm (25-16 mesh), a coating film of a water-soluble polymer and an antifungal agent, and a seal coating layer wherein the residual concentration of dichloromethane is reduced by microwave drying (page 10, lines 31 to 38).
PCT Application WO 98/42318 to Vandecruys et al., (assigned to Janssen Pharmaceutica) describes 30-60 mesh beads having a core coated with itraconazole or saperconazole, which beads may likewise be used to produce dosage forms of these drugs. To prepare the beads the drug coating solution is, again, dissolved into a suitable solvent system. Again the only solvent system described is one comprising methylene chloride and an alcohol, and it is stated that the methylene chloride should comprise at least 50% by weight of the solvent system (see page 8, lines 32-34 therein).
U.S. application Pat. No. 6,039,981 teaches an antifungal composition for oral administration comprising a fused mixture of itraconazole and phosphoric acid, a pharmaceutically acceptable carrier and a surfactant. Heating of the mixture is done at 100 to 170° C. to obtain a homogeneous mixture (Column 3, lines 16-18). Although example 8 provides a composition that needs to be loaded on to sugar spheres, no dissolution data or stability information in terms of acid and sugar spheres interaction (caramelization) was discussed. The example 8 composition also does not produce a mixture that could be sprayed onto sugar or microcrystalline spheres when the experiment was repeated in our laboratories.
Accordingly, there remains a need for new ways to produce oral dosage forms of water insoluble drugs that utilize coated particles, but do not require the use of methylene chloride or other objectionable solvents during the manufacture thereof. A process that can be industrially applicable, and preferably does not use temperatures above 100° C., that are needed for making fusion mixtures. A process that prevents interaction between core particles and acid or base ingredients or acidity as contributed by Active Pharmaceutical Ingredient itself is needed.